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From GWAS to drug screening: repurposing antipsychotics for glioblastoma
Wei-Zhi Lin1, Yen-Chun Liu2, Meng-Chang Lee3
1Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Sec. 6, Minquan E. Rd., Neihu Dist., Taipei City, 11490, Taiwan.
Background:
Glioblastoma is currently an incurable cancer. Genome-wide association studies have demonstrated that 41 genetic variants are associated with glioblastoma and may provide an option for drug development.
Methods:
We investigated FDA-approved antipsychotics for their potential treatment of glioblastoma based on genome-wide association studies data using a 'pathway/gene-set analysis' approach.
Results:
The in-silico screening led to the discovery of 12 candidate drugs. DepMap portal revealed that 42 glioma cell lines show higher sensitivities to 12 candidate drugs than to Temozolomide, the current standard treatment for glioblastoma.
Conclusion:
In particular, cell lines showed significantly higher sensitivities to Norcyclobenzaprine and Protriptyline which were predicted to bind targets to disrupt a certain molecular function such as DNA repair, response to hormones, or DNA-templated transcription, and may lead to an effect on survival-related pathways including cell cycle arrest, response to ER stress, glucose transport, and regulation of autophagy. However, it is recommended that their mechanism of action and efficacy are further determined.
Insights
FDA-approved antipsychotics show promise for treating glioblastoma, an incurable cancer. In-silico screening identified 12 candidates, with Norcyclobenzaprine and Protriptyline demonstrating significant potential in glioma cell lines.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Glioblastoma is a currently incurable brain cancer.
- Genome-wide association studies identified 41 genetic variants linked to glioblastoma risk.
- These variants offer potential targets for novel drug development.
Purpose of the Study:
- To investigate FDA-approved antipsychotics as potential glioblastoma treatments.
- To leverage genome-wide association studies data and pathway/gene-set analysis for drug discovery.
Main Methods:
- Utilized a pathway/gene-set analysis approach on genome-wide association studies data.
- Performed in-silico screening of FDA-approved antipsychotics.
- Assessed drug sensitivity in 42 glioma cell lines using the DepMap portal.
Main Results:
- Identified 12 candidate drugs with potential glioblastoma treatment applications.
- Observed significantly higher sensitivity in 42 glioma cell lines to these 12 candidates compared to Temozolomide.
- Norcyclobenzaprine and Protriptyline exhibited particularly high sensitivity, predicted to disrupt critical molecular functions.
Conclusions:
- FDA-approved antipsychotics, specifically Norcyclobenzaprine and Protriptyline, show therapeutic potential for glioblastoma.
- These drugs may act by disrupting DNA repair, hormone response, or transcription, impacting cell cycle and survival pathways.
- Further research is recommended to elucidate their precise mechanism of action and confirm efficacy.
